ETIOLOGY OF TREATMENT-INDUCED SECONDARY LEUKEMIA

治疗引起的继发性白血病的病因

• 批准号: 3093782
• 负责人: BERNARD S. STRAUSS
• 金额: $ 95.94万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-01 至 1991-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3093782
• 关键词: chromosome translocation; drug carcinogenesis; genetic mapping; leukemia; lymphocytic leukemia; lymphoma; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplasm /cancer radiation therapy

We propose to continue and expand our studies on the etiology of treatment- related acute nonlymphocytic leukemia (t-ANLL). Additional support is requested for two continuing and one new project. We have found that individuals being treated for Hodgkin;s disease (HD) and non-Hodgkin's lymphoma (NHL) as well as individuals with t-ANLL have low alkylguanine methyltransferase (AGT) activity as compared with healthy controls or individuals with ANLL de novo. We propose to test the hypothesis that low AGT activity is related to the development of t-ANLL. We will test AGT levels in patients undergoing radiation therapy for HD as controls and will follow AGT activity in individuals receiving high-dose chemotherapy with BCNU. We plan to develop an antibody to AGT to study the heterogeneity of this protein in lymphoid cells. Studies on mutability using both a chromosomal gene and an Epstein-Barr virus (EBV)-based plasmid will be carried out in a series of isogenic lymphoblastoid lines of differing AGT content to determine the relationship between activity and mutability after treatment with MNNG and BCNU. Chromosome breakage measured cytologically and biochemically will be correlated with AGT activity to test the hypothesis that low levels of AGT lead to higher mutability. In a new program, we propose to identify and isolate the putative genes located on chromosome 5. whose altered function as a result of recessive mutations (e.g., chromosome deletions, point mutations, and submicroscopic deletions of the type studied in the first programs) plays a role in the pathogenesis of ANLL. To accomplish this aim, the investigators will develop a physical linkage map of genes and anonymous sequences in the critical region of 5q; this map will be used to examine the DNA derived from leukemia cell of patients with deletions of 5q in order to identify submicroscopic deletions or other DNA rearrangements in the "normal" chromosome 5 homologue thereby identifying candidate genes for homozygous inactivation. These studies added to the continuing work of the Program will provide more definitive understanding of the etiology of t-ANLL.

我们建议继续和扩大我们对治疗病因的研究- 相关急性非淋巴细胞白血病（t-ANLL）。更多支助 要求提供两个持续项目和一个新项目。我们发现 正在接受何杰金氏病（HD）和非何杰金氏病治疗的个体 淋巴瘤（NHL）以及t-ANLL个体具有低烷基鸟嘌呤 甲基转移酶（AGT）活性与健康对照相比，或 ANLL de novo患者。我们建议测试的假设，低 AGT活性与t-ANLL的发生有关。我们将测试AGT 作为对照，接受HD放射治疗的患者中的水平， 跟踪接受高剂量化疗的个体中的AGT活性， BCNU.我们计划开发抗AGT的抗体，以研究AGT的异质性。 淋巴细胞中的这种蛋白质。同时使用a和b的突变性研究 染色体基因和基于EB病毒（EBV）的质粒将被 在一系列不同AGT的同基因淋巴母细胞系中进行 内容，以确定活动和可变性之间的关系， 用MNNG和BCNU治疗。细胞学测量的染色体断裂 生物化学将与AGT活性相关，以测试 低AGT水平导致高突变性的假说。在一个新 程序，我们建议识别和分离位于 5号染色体。由于隐性突变， (e.g.,染色体缺失、点突变和亚显微缺失 在第一个项目中研究的类型）在发病机制中起作用 的ANLL。为了实现这一目标，研究人员将开发一种物理 5 q关键区基因和无名序列的连锁图; 该图谱将用于检测来自白血病细胞的DNA， 5 q缺失的患者，以鉴定亚显微缺失 或其他DNA重排的“正常”5号染色体同源物， 鉴定纯合失活的候选基因。这些研究 加入该计划的持续工作将提供更明确的 了解t-ANLL的病因。